PI3K inhibition by BKM120 results in anti-proliferative effects on corticotroph tumor cells

2022 ◽  
Author(s):  
H. A. Oliveira ◽  
A. C. Bueno ◽  
R. S. Pugliesi ◽  
R. M. P. da Silva Júnior ◽  
M. de Castro ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Pi3k Inhibition

PIK3IP1 Inhibition of PI3K in G1 Arrest Induced By CDK4 Inhibition Reprograms MCL for Ibrutinib Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 610-610 ◽  
Author(s):  
Maurizio Di Liberto ◽  
Xiangao Huang ◽  
Olivier Elemento ◽  
Ken Eng ◽  
Kristie A. Blum ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tumor Cells ◽  
Research Funding ◽  
G1 Arrest ◽  
Primary Resistance ◽  
Durable Response ◽  
Dual Targeting ◽  
Pi3k Inhibition ◽  
Ibrutinib Resistance ◽  
Cdk4 Inhibition

Abstract Inhibition of CDK4/6 has emerged as a promising therapy for diverse human cancers. Mantle cell lymphoma (MCL), in which aberrant cyclin D1 expression and CDK4 activity underlie unrestrained proliferation of tumor cells, remains incurable. Targeting Bruton tyrosine kinase (BTK) with ibrutinibin recurrent MCLhas unprecedented single agent activity, with a completion remission (CR) rate of 21%. However, progression on ibrutinib is virtually universal in MCL and is associated with aggressive proliferation of tumor cells and a dismal clinical outcome. By longitudinal integrated RNA- and exome-seq analysis, we previously discovered a mutation in the ibrutinib binding site (BTKC481S) in MCL that was specific to relapse from a durable response, but absent in both primary resistance and resistance following a transient response. Irrespective of mechanism, ibrutinib resistance was associated with enhanced PI3K activation as determined by Western blotting of MCL cells isolated from serial biopsies. Induction of prolonged early G1 arrest (pG1) by selective inhibition of CDK4 with palbociclib sensitized to PI3K inhibition independent of this BTK mutation and to ibrutinib when the wild type BTK was retained. In both cases, synergistic killing appears to occur via cooperative inactivation of PI3K. Collectively, our data suggest that dual inhibition of CDK4 and BTK or PI3K restrain the expansion of resistant clones or even eliminate them to deepen or prolong the clinical response to targeting BTK. To test this hypothesis, we initiated a phase I clinical trial of palbociclib plus ibrutinib in recurrent MCL patients in August of 2014. All 5 dose levels included ibrutinib daily and palbociclib administered on days 1-21 of each 28-day cycle (Figure 1). Based on an intent-to-treat analysis of 18 patients, 12 (67%) patients have responded to treatment including 8 (44%) complete responses (CR). The median time to CR was 3 cycles and no responding patients have progressed on study. The therapy was well tolerated (see ASH abstract by Martin et al for clinical information). RNA- and exome-seq were performed to assess the genomic alternations and gene expression on purified MCL cells from samples before therapy, on progression and on treatment from PR patients. Initial analysis did not detect non-synonymous mutation in CDK4, CCND1, or genes in the BCR or PI3K signaling pathway. Hemizygous deletion of Rb, p53, ATM and the INK4A/B locus and amplification of PIK3CA and PIK3CB occurred in 30-50 % of patients before therapy. These copy number variations were predominantly associated with primary resistance (4 subjects) but did not preclude CR or PR. By contrast, expression of PIK3IP1, a putative PI3K inhibitor, was markedly reduced on progression in all primary resistant patients, but not in the PR patient. Function studies demonstrated that PIK3IP1 was required for pG1 sensitization to BTK and PI3K inhibition in MCL cells in vitro. Moreover, PIK3IP1 was induced in pG1 together PI3K inhibition in MCL cells in patients responding to palbociclib alone in a separate clinical trial (Martin, DiLiberto et al, unpublished), suggesting that PIK3IP1 mediates pG1 reprogramming. In summary, the high CR rate and durability support our hypothesis that induction of prolonged early G1 arrest by CDK4 inhibition reprograms MCL cells for deepened and durable targeting of BTK in MCL. Our data further suggest inhibition of PI3K by PIK3IP1 as a potential mechanism to overcome ibrutinib resistance. A phase II multi-center clinical trial is planned to further elucidate the genes and mechanisms that discriminate sensitivity from resistance to dual targeting of CDK4 and BTK. Figure 1. Dual targeting of CDK4 with palbociclib and BTK with ibrutinib in recurrent MCL Figure 1. Dual targeting of CDK4 with palbociclib and BTK with ibrutinib in recurrent MCL Disclosures Blum: Pharmacyclics: Research Funding. Ruan:Pharmacyclics: Research Funding, Speakers Bureau. Martin:Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy; Acerta: Consultancy; Teva: Research Funding.

scholarly journals ERK2-dependent reactivation of Akt mediates the limited response of tumor cells with constitutive K-RAS activity to PI3K inhibition

2013 ◽  
Vol 15 (3) ◽  
pp. 317-328 ◽  
Author(s):  
Mahmoud Toulany ◽  
Minjmaa Minjgee ◽  
Mohammad Saki ◽  
Marina Holler ◽  
Friedegund Meier ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Pi3k Inhibition

scholarly journals Androgen Receptor-Induced Integrin α6β1 and Adhesion to Laminin Promotes Survival and Drug Resistance in Castration-Resistant Prostate Cancer through BNIP3

2018 ◽  
Author(s):  
Eric A. Nollet ◽  
Sourik S. Ganguly ◽  
Veronique V. Schulz ◽  
Anne Cress ◽  
Cindy K. Miranti
Keyword(s):  
Androgen Receptor ◽  
Tumor Cells ◽  
Castration Resistant Prostate Cancer ◽  
Bcl2 Family ◽  
Castration Resistant ◽  
Pi3k Inhibition ◽  
Survival Pathway ◽  
Prostate Cancers ◽  
Integrin Α6β1 ◽  
Resistant Cells

ABSTRACTAlthough castration-resistant prostate cancers no longer respond to anti-androgen therapies, the androgen receptor (AR) is still required to promote tumor survival. However, the signaling pathways downstream of AR that promote this survival are not well known. We recently identified an AR-dependent survival pathway whereby AR induction of integrin α6β1 and adhesion to laminin activates NF-kB/RelA signaling and Bcl-xL. This pathway acts in parallel with the PI3K/Akt pathway in Pten-null tumor cells such that combined inhibition of both PI3K and integrin α6β1 is required to kill tumor cells adherent to laminin. However, PTEN-null castration-resistant tumors were not effectively inhibited by this combination. We discovered that BNIP3, a hypoxia-induced BH3-only, pro-mitophagic Bcl2 family member, is induced by androgen in castration-resistant cells through integrin α6β1 signaling to HIF1α. Furthermore, castration-resistant cells adherent to laminin were much more efficient at inducing autophagy in response to androgen. Androgen blocked the ability of the PI3K inhibitor PX-866 to kill castration-resistant tumors, but this was reversed by loss of BNIP3. Although BNIP3 was dispensable for androgen-induced autophagy, its mitophagy function was required for BNIP3 to promote resistance to PI3K inhibition. Thus, adhesion to laminin triggers signaling through AR/α6β1/HIF1α in castration-resistant cells to drive the expression of BNIP3 and cooperates with AR/α6β1-mediated autophagy, both of which contribute to PI3K resistance through induction of mitophagy.

Membranous alterations in the cytoplasm and nucleus in a primitive neuroectodermal tumor of the brain

1978 ◽  
Vol 36 (2) ◽  
pp. 628-629
Author(s):  
C. N. Sun ◽  
C. Araoz ◽  
H. J. White
Keyword(s):  
Nuclear Envelope ◽  
Tumor Cells ◽  
Osmium Tetroxide ◽  
Primitive Neuroectodermal Tumor ◽  
Uranyl Acetate ◽  
Neuroectodermal Tumor ◽  
Annulate Lamellae ◽  
Lead Citrate ◽  
Thin Sections ◽  
The Brain

The ultrastructure of a cerebral primitive neuroectodermal tumor has been reported previously. In the present case, we will present some unusual previously unreported membranous structures and alterations in the cytoplasm and nucleus of the tumor cells.Specimens were cut into small pieces about 1 mm3 and immediately fixed in 4% glutaraldehyde in phosphate buffer for two hours, then post-fixed in 1% buffered osmium tetroxide for one hour. After dehydration, tissues were embedded in Epon 812. Thin sections were stained with uranyl acetate and lead citrate.In the cytoplasm of the tumor cells, we found paired cisternae (Fig. 1) and annulate lamellae (Fig. 2) noting that the annulate lamellae were sometimes associated with the outer nuclear envelope (Fig. 3). These membranous structures have been reported in other tumor cells. In our case, mitochondrial to nuclear envelope fusions were often noted (Fig. 4). Although this phenomenon was reported in an oncocytoma, their frequency in the present study is quite striking.

Ulcerogenic Tumors of the Pancreas

1968 ◽  
Vol 26 ◽  
pp. 186-187
Author(s):  
J. C. Garancis ◽  
J. F. Kuzma ◽  
S. D. Wilson ◽  
E. H. Ellison
Keyword(s):  
Endoplasmic Reticulum ◽  
Tumor Cells ◽  
Islet Cell ◽  
Disease Process ◽  
Central Core ◽  
Islet Cell Tumors ◽  
Opaque Zone ◽  
Granular Form ◽  
Zollinger Ellison Syndrome

It has been proposed that a gastrin-like hormone elaborated by non-beta islet tumors of the pancreas may be responsible for a fulminating ulcer diathesis. Subsequently, a potent gastric secretagogue was isolated from ulcerogenic tumors of the pancreas. This disease process is known now as “Zollinger-Ellison syndrome”.In our studies of two cases of Zollinger-Ellison syndrome, pancreatic lesions were identified as alpha islet cell tumors (Fig. 1). Tumor cells were fairly uniform. The sizes of the alpha granules were not significantly different, but their number and distribution varied greatly from one cell to another. Each granule consisted of a round, highly dense central core, separated from the limiting membrane by an opaque zone. The granular form of the endoplasmic reticulum was particularly prominent. Numerous mitochondria, round or elongated, were dispersed throughout the cytoplasm. Individual or clusters of lysosomes were observed in the majority of cells.

Glucose metabolism in cancer cells: immunogold localization of hexokinase to the outer mitochondrial membrane

1995 ◽  
Vol 53 ◽  
pp. 1044-1045
Author(s):  
Krishan K. Arora ◽  
Glenn L. Decker ◽  
Peter L. Pedersen
Keyword(s):  
Tumor Cells ◽  
Mitochondrial Membrane ◽  
Present Report ◽  
Large Fraction ◽  
Mitochondrial Fraction ◽  
Immunogold Labeling ◽  
Outer Mitochondrial Membrane ◽  
Immunogold Localization ◽  
Hexokinase Activity ◽  
Normal Tissues

Hexokinase (ATP: D-hexose 6-phophotransferase EC 2.7.1.1) is the first enzyme of the glycolytic pathway which commits glucose to catabolism by catalyzing the phosphorylation of glucose with ATP. Previous studies have shown diat hexokinase activity is markedly elevated in rapidly growing tumor cells exhibiting high glucose catabolic rates. A large fraction (50-80%) of this enzyme activity is bound to the mitochondrial fraction (1,2) where it has preferred access to ATP (3). In contrast,the hexokinase activity of normal tissues is quite low, with one exception being brain which is a glucose-utilizing tissue (4). Biochemical evidence involving rigorous subfractionation studies have revealed striking differences between the subcellular distribution of hexokinase in normal and tumor cells [See review by Arora et al (4)].In the present report, we have utilized immunogold labeling techniques to evaluate die subcellular localization of hexokinase in highly glycolytic AS-30D hepatoma cells and in the tissue of its origin, i.e., rat liver.

Sequential detection of mRNA for the chemokine IL-8 and macrophages (F4/80) in human melanoma

1995 ◽  
Vol 53 ◽  
pp. 1008-1009
Author(s):  
C.D. Bucana ◽  
R. Sanchez ◽  
R. Singh ◽  
I.J. Fidler
Keyword(s):  
Tumor Cells ◽  
Nude Mice ◽  
Constitutive Expression ◽  
Metastatic Potential ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Angiogenic Factor ◽  
Infiltrating Cells ◽  
Immunoperoxidase Assay ◽  
Multifunctional Cytokine

The purpose of this study was to demonstrate by ISH the presence of IL-8 mRNA, and by immunohistochemistry (IHC) the presence of the chemokine IL-8 and the distribution of infiltrating macrophages in subcutaneous melanomas in the same tumor. IL-8 is a multifunctional cytokine produced by melanoma cells, activated macrophages and monocytes and it has been shown to be a growth and angiogenic factor for tumor cells. More recently it was shown that constitutive expression of IL-8 correlated directly with metastatic potential of human melanoma cells in nude mice. IL-8 content of a solid tumor as determined by Western blot analysis does not take into account the contribution of macrophages. Previous studies showed that murine tumors contain many infiltrating cells interspersed among tumor cells whereas human tumors growing in nude mice exhibit macrophages at the periphery or between tumor islands. In this study we demonstrate the expression of IL-8 and the distribution of macrophages by immunoperoxidase assay and IL-8 mRNA by ISH.

Temporal and spatial interrelationships of confronting cisternae to nuclear envelope

1992 ◽  
Vol 50 (1) ◽  
pp. 930-931
Author(s):  
John R. Palisano
Keyword(s):  
Endoplasmic Reticulum ◽  
Nuclear Envelope ◽  
Tumor Cells ◽  
Hela Cells ◽  
Microscopic Investigation ◽  
Electron Microscopic Investigation ◽  
Serial Sections ◽  
Electron Microscopic ◽  
Fetal Rat ◽  
Temporal And Spatial

Although confronting cistemae (CC) have been observed in a variety of tumor cells and normal fetal rat, mouse, and human epithelial tissues, little is known about their origin or role in mitotic cells. While several investigators have suggested that CC arise from nuclear envelope (NE) folding back on itself during prophase, others have suggested that CC arise when fragments of NE pair with endoplasmic reticulum. An electron microscopic investigation of 0.25 um thick serial sections was undertaken to examine the origin of CC in HeLa cells.

Genomic alterations of micrometastatic tumor cells in patients with operable esophageal carcinoma

2001 ◽  
Vol 120 (5) ◽  
pp. A344-A344
Author(s):  
N STOECKLEIN ◽  
M PETRONIO ◽  
T BLANKENSTEIN ◽  
S HOSCH ◽  
A ERBERSDOBLER ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Tumor Cells ◽  
Genomic Alterations
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